(2-oxo-azetidino)benzophenone compounds

ABSTRACT

The invention is directed to N-aryl-2-benzoyl- Alpha oxocyclopolymethylene amines which have anticonvulsant properties particularly in preventing convulsions such as are produced by metrazol or electric shock.

United States Patent [19'] Wei et al.

[ 1 Jan. 30, 1973 [54] (Z-OXD-AZETIDINO)BENZOPHENONE COMPOUNDS 75Inventors: Peter H. L. Wei, Springfield, Pa.,

Stanley C. Bell, Penn Valley, Pa.

[62] Division of Ser. No. 735,534, June l0, l968, Pat. No.

[52] US. Cl. ..260/239 A [51] Int. Cl. ..C07d 25/02 [58] Field of Search..260/239 A Primary ExaminerAlto n D. Rollins Attorney-Vito VictorBellino et al.

[57] ABSTRACT The invention is directed toN-aryI-Z-benzoyl-a-oxocyclopolymethylene amines which haveanticonvulsant properties particularly in preventing convulsions such asare prodl'lced by metrazol or electric shock.

' 2 Claims, N0 Drawings (2-0XO-AZE'IlDlN0)BENZOPHENONE COMPOUNDS Thisapplication is a division of our application Ser. No. 735,534, filedJune 10, 1968, now US. Pat. No. 3,644,401, dated Feb. 22, 1972.

This invention relates to new and novel N-aryl-Z-benzoyl-a-oxo-cyclopolymethylene amines and to a process for theirpreparation.

The compounds within the purview of the present invention areexemplified by those having the following qrmyla;

I Where R and R are hydrogen, halogen, lower alkyl,

- lower alkoxy or sulfamoyl;

R is hydrogen, halogen, lower alkyl and lower alkoxn is an integer from2 to about 4, with the proviso that R or R is in the 60'-position when nis 2.

As used herein, the terms lower alk'yl, lower alkoxy and the like,describe groups containing from one to about eight carbon atoms.

The compounds of this invention are depicted by structural formula (I)and generically designated as N-aryl-2-benzoyl-a-oxocyclopolymethyleneamines." A typical example of these compounds when n 2 is 3,5-dichloro-2-( 2-oxol -azetidinyl )benzophenone;

The new and novel compounds of this invention may be prepared by theprocess which is hereinafter schematically illustrated.

Where R R and n are as defined above; and X is q inerb omeandiod ue, a,

To prepare the N-aryl- -benzoyl-a-oxocyclopolymethylene amines (I) ofthe present invention, a two step procedure is utilized. In the firststep a 2-benzoylaniline (ll) is contacted with a haloalkanoyl halide(ill) in an organic solvent, such as chloroform, at a temperature rangefrom about 0C. up to the reflux temperature for a period of about 1 toabout 4 hours. When the reaction is complete, the resulting intermediatecompound 2-benzoylhaloalkanoyl anilide (IV) may be separated andrecovered by well known means. For example, the reaction mixture isallowed to stand until separation of the product is complete.Thereafter, the solvent may be removed and the residual solid collectedand washed with a small amount of organic solvent such as chloroform,hexane, benzene or ether, and the solid recrystallized from anappropriate solvent such as ethanol, acetonitrile or benzene.

When n 2, the 6'-position of .the 2-benzoylhaloalkanoylanilide (IV) mustbe blocked prior to carrying out the second step.

To prepare the N-aryl-2-benzoyl-a-oxocyclopolymethylene amines (l) ofthis invention, the above prepared 2-benzoylhaloalkanoyl anilide (IV) isheated with an alkali metal cyanide in an alkanol in the presence of acatalyst, for example sodium iodide, at a temperature range from about50C. to about C., preferably the reflux temperature, for a period ofabout I to 20 hours affording the product aN-aryl-2-benzoyla-oxocyclopolymethylene amine (I) of this invention. Theproduct may be separated and'recovered by well known techniques. Forinstance, the inorganic material may be filtered off, the filtrateevaporated to dryness, and the residual solid recrystallized from asuitable organic solvent, such as ethanol. Preferably, this reaction isconducted with potassium cyanide, in ethanol, in the presence of acatalytic amount of sodium iodide, at reflux temperatures for about 6-20hours.

The new and novel N-aryl-2-benzoyl-a-oxocyclopolymethylene amines (l) ofthe present invention have exhibited anticonvulsant properties,particularly as they prevent convulsion produced by metrazol or electricshock.

In the pharmacological evaluation of the biological activity of thecompounds of this invention, the in vivo effects are tested as follows.The compound is administered orally to three mice (14 to 24 grams) ateach of the following doses: 400, 127,40 and 12.7 mg./kg. The animalsare watched for a minimum of 2 hours during which time signs of generalstimulation, (i.e., increased spontaneous motor activity, hyperactivityon tactile stimulation, twitching), general depression (i.e., decreasedspontaneous motor activity, decreased respiration)autonomic activity(i.e., miosis, mydriasis, diarrhea) are noted. The experiment isterminated by subjecting each animal to a maximal electroshock to testfor anti-convulsant activity. If the compound demonstrates no activityfollowing oral administration, the procedure is repeated followingintraperitoneal administration. The compounds of the present inventionprevented convulsions due to electroshock at an oral dose of 400milligrams per kilogram of host body weight. 4

Anti-metrazol activity is determined as follows. Compounds at a numberof dose levels are administered orally to groups of six mice (3 malesand 3 females). One hour later the animals are challenged with metrazol125 mg./kg. i.p. The incidence of clonic and tonic convulsions anddeaths is observed for onehalf hour. Protection against convulsions anddeath is determined by comparison with controls run simultaneously.

The compounds of this invention in the above test procedures preventedthe convulsant effects of electroshock and metrazol and have acalculated ED, of 201 to 400 milligrams per kilogram of hose weight. Theeffective dose for 50 percent of the hosts is termed ED,,,,. subliguallyWhen the compounds of this invention are employed as described above,they may be administered alone or in combination with pharmacologicallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmacological practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch excipients as starch, milk, sugar, certain types of clay and soforth. They may be administered sublingually in the form of troches-orlozenges in which the active ingredient is mixed with sugar and cornsyrups; and then dehydrated sufiiciently to make it suitable forpressing into a solid form. They may be administered orally in the formof solutions or they may be injectedparenterally, that is,*intramuscularly, intravenou'sly or subcutaneously. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present pharmacological agents will vary with the formof administration and the particular compound chosen. Furthermore, itwill vary with the particular subject under treatment. Generally,treatment is initiated with .small dosages substantially less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. it will generally be found that when the composition. isadministered orally, larger quantities of the active agent will berequired to produce the same effect as a smaller quantity givenparenterally. In general, the compounds of this invention are mostdesirably administered at a concentration level that will generallyafford effective results without causing any harmful or deleterious sideeffects.

in order more clearly to disclose the nature of the present invention,specific examples of the practice of the invention are hereinaftergiven. it should be understood, however, that this is'done solely by wayof example and is intended neither to delineate the scope ofthe-invention nor to limit the ambit of the appended claims. I

EXAMPLE 1 The following example illustrates the preparation of2'-benzoyl-3,4f,6'-trichloropropionanilide and 3,5- dichloro-2-( 2-oxol-azetidinyl )benzophenone.

Step A A solution of 40 grams (g.) [0.15 moles (m.)] of 2-benzoyl-4,6-dichloroaniline and 25 g. (0.195 m.) of 3- chloropropionylchloride in 400 ml. of chloroform is heated ina water bath at 60C. for1% hours (hr,) a nd let stand at room temperature overnight. The soiventis removed and residual solid collected and washed with a small amountof chloroform. Recrystallization from ethanol affords pure2'-benzoyl-3,4,6- trichloropropionanilide weighing 49 g. and melting at167-9C.

Based on the formula C l-l ChNO, it is calculated that the elementalanalysis by weight would be 53.91 percent carbon, 3.39 percent hydrogen,3.93 percent nitrogen and 29.84 percent chlorine. The product isanalyzed and the content is found to be 54.37 percent carbon, 3.47percent hydrogen, 4.27 percent nitrogen and 29.7 percent chlorine. Theforegoing may be expressed:

Analysis calculated for C l-i,,Cl -,NO,: C, 53.91; H,

Found: C, 54.37; H, 3.47; Cl, 29.7; N, 4.27. Step B A solution of 10.7g. (0.030 m.) of2'-benzoyl-3,4'-6' -trichloropropionanilide and 2.34 g.(0.036 m.) of potassium cyanide in 220 ml. of percent ethanol is heatedto reflux in the presence of a catalytic amount of sodium iodide for 17hours. Inorganic material is filtered off and, after removal of thesolvent, the residual solid is recrystallized to afford 5.5 g. of3,5-dichloro-2- (2-oxo-l-azetidinyl)benzophenone. When furtherrecrystallized from benzene the product has a melting point of l 12-l14C.

Analysis calculated for CIGHICI2NO2: C, 60.02; H,

3.46; Cl, 22.15; N, 4.38. Found: C, 60.57; H, 3.75; Cl, 218; N, 4.06.

ml. of water, 21.5 g. of product having a melting point of l25-l27C. isobtained. Themelting point remains the same after recrystallization fromethanol.

Analysis calculated for C l-i ClNO z C,. 68.12; H,

4.71; Cl, 11.83; N, 4.67. Found: C, 67.98; H, 4.55; Cl, 12.0; N, 4.63.

EXAMPLES 3l4 Proceeding as described in Example 1, but substituting thefollowing starting materials for 2'-benzoyl-3,4',6'-trlchloropropionanilide, the following products are obtained:

Starting Material Product 3 2'-(p-chlorobenzoyl)-4,4',

tribromobutyranilide l-l 2-(p-chlorobenzoyl)- 4,6-dibromophenyl1-2-2-benzoyl-5-bromo-3',4'- difluorovaleranilide2-(p-methylbenzoyl)-3,4,6'- triiodopropionanilide2'-benzoyl-4-bromo-3,6'- dichloropropionanilide2'-benzoyl-4-chloro4',6'- dimethylbutyranilide-bromo-4-butyl-2-(mmethoxybenzoyl)-6'-fluorovaleranilide3-chloro-4'-ethyl-2'-(pethylbenzoyl)-6'-sulfamoylpropionanilide2'-benzoyl-3-ehloro-4',6'- dimethoxypropionanilide4-bromo-2'-(o-bromobenzoyl)- 4',6'-dibutoxybutyranilide2-benzoyl-5-chloro-6'- ethoxy-4'-propoxyvaleranilide 2-( p-butoxybenzoyl)-3 fluoro-3-iodo-5 '-methylpropionanilide 2'-benzoyl-3,4-dichloro-6'-methoxypropionanilide pyrrolidinone l -piperidinyl benzophenone3,5-diiodo-4-methyl-2- (2-oxol-azetidinyl) benzophenone 5-brorno-3-chloro-2- (l-oxo-l -azetidinyl)- benzophenone 3,5-dirnethyl-2-(2-oxol-pyrrolidinyl) benzophenone 5-butyl-3-fluoro-3 rnethoxy-2-(2-oxo-l piperidinyl)benzophenone 4,5-diethyl-3- sulfamoyl-2-(2-oxol-azetidinyl)benzophenone 3,5-dimethoxy-2-( 2-oxol-azetidinyD-benmphenone 2-bromo-3,5-dibutoxy- 2-( 2-oxol -pyrrolidinyl) benzophenone3-ethoxy-5 -propoxy-2- (2-oxo-l -piperidinyl) benzophenone4'-butoxy-6-fluoro-4- methyl-2-( 2-oxol azetidinynbenzophenoneS-chloro-3-rnethoxy- 2-( 2-oxol-azetidinyl benzophenone The terms andexpressions which have been employed are used as terms of descriptionand not of limitation, and there is no intention in the use of suchterms and expressions of excluding any equivalents of the features shownand described or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention claimed.

What is claimed is:

1. A compound selected from those having the formula 0:0 I I Rom) Nwhere R and R are selected from the class consisting of hydrogen,halogen, lower alkyl having from one to eight carbon atoms, lower alkoxyhaving from one to eight carbon atoms, and sulfamoyl; and R is selectedfrom the class consisting of hydrogen,

halogen, lower alkyl having from one to eight carbon atoms, and loweralkoxy having from one to eight carbon atoms. 2. A compound as definedin claim 1 which is- 3,5- dichloro-2-(2-oxo-l-azetidinyl)benzophenone.

33 UNETEE STA'E'ES PATENT oFmcE 4 QERTEHQATE @F QQREQ'HQN Patent No.?.7l +.l +7 Dated Januarv' 30. 197? Inventor(s) Petei' H. L. Wei andStan'lev 0,: Bell It is certified that errorappears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

At column 6 lines 10-19 the structural formula of Claim "1 should readas follows:-

Signed and sealed this 10th day of July 1973.

Attest:

EDNARD MELETICHER'JRQ Rene Tegtmeyer Attestlng Officer ActingCommissioner of Patents

1. A compound selected from those having the formula 